In Situ Liver Expression of HBsAg/CD3-Bispecific Antibodies for HBV Immunotherapy

Robert L. Kruse, Thomas Shum, Xavier Legras, Mercedes Barzi, Frank P. Pankowicz, Stephen Gottschalk, Karl Dimiter Bissig

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Current therapies against hepatitis B virus (HBV) do not reliably cure chronic infection, necessitating new therapeutic approaches. The T cell response can clear HBV during acute infection, and the adoptive transfer of antiviral T cells during bone marrow transplantation can cure patients of chronic HBV infection. To redirect T cells to HBV-infected hepatocytes, we delivered plasmids encoding bispecific antibodies directed against the viral surface antigen (HBsAg) and CD3, expressed on almost all T cells, directly into the liver using hydrodynamic tail vein injection. We found a significant reduction in HBV-driven reporter gene expression (184-fold) in a mouse model of acute infection, which was 30-fold lower than an antibody only recognizing HBsAg. While bispecific antibodies triggered, in part, antigen-independent T cell activation, antibody production within hepatocytes was non-cytotoxic. We next tested the bispecific antibodies in a different HBV mouse model, which closely mimics the transcriptional template for HBV, covalently closed circular DNA (cccDNA). We found that the antiviral effect was noncytopathic, mediating a 495-fold reduction in HBsAg levels at day 4. At day 33, bispecific antibody-treated mice exhibited 35-fold higher host HBsAg immunoglobulin G (IgG) antibody production versus untreated groups. Thus, gene therapy with HBsAg/CD3-bispecific antibodies represents a promising therapeutic strategy for patients with HBV.

Original languageEnglish (US)
Pages (from-to)32-41
Number of pages10
JournalMolecular Therapy Methods and Clinical Development
Volume7
DOIs
StatePublished - Dec 15 2017
Externally publishedYes

Keywords

  • T cell
  • bispecific antibody
  • gene therapy
  • hepatitis B virus
  • immunotherapy
  • liver
  • viral hepatitis

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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